Neurodegeneration means progressive loss of structure or function of neurons, including death of neurons. Neurons are the building blocks of the nervous system which includes the brain and spinal cord. Neurons normally don't reproduce or replace themselves, so when they become damaged or die they cannot be replaced by the body. Examples of neurodegenerative diseases include Parkinson's, Alzheimer's, Huntington's disease, spinal cord injury, stroke and amyotrophic lateral sclerosis.
Neurodegenerative diseases are incurable and debilitating conditions that result in progressive degeneration and/or death of nerve cells. This causes problems with movement (called ataxias), or mental functioning (called dementias). Many neurodegenerative diseases are caused by traumas directed at brain or spinal cord, or either hereditary or sporadic genetic mutations. The greatest risk factor for neurodegenerative diseases is aging.
Inflammation is a defense reaction against diverse insults, designed to remove noxious agents and to inhibit their detrimental effects. It consists of molecular and cellular mechanisms and an intricate network of controls to keep them in check. In neurodegenerative diseases, inflammation may be triggered by the accumulation of aggregated or otherwise modified proteins, by signals emanating from injured neurons, or by imbalances between pro- and anti-inflammatory processes.
Spinal Cord Injury
Spinal cord injury (SCI) is classified as damage to the spinal cord caused by trauma, instead of disease, with symptoms ranging from pain to paralysis to incontinence. Any injury that involves the head, pelvic fractures, penetrating injuries in the area of the spine or injuries that result due to a fall from height, may result in spinal cord damage. The most common causes of SCI are motor vehicle accidents, falls and violence.
In the US, there are an estimated 12,000 new cases of SCI each year, with approximately 260,000 individuals afflicted by SCI. In Europe, there are estimated to be roughly 9,000 new SCI cases per year. Most incidences of SCI occur in people between the ages of 16-30 and hence healthcare expenses can be considerable, varying depending upon the severity of injury. Estimated lifetime costs for a tetraplegic patient are greater than a $1,000,000. These figures do not include any indirect costs, such as losses in salary, which are estimated to be approximately $64,000 per year.
Treatment options for SCI are extremely limited, with physical therapy a major treatment modality. Methylprednisolone, which helps to reduce swelling in the spinal cord, is widely prescribed as an off-label drug, but does not serve most patients needs. There are currently no therapies to alleviate, or repair, the incurred damage to the spinal cord. Very few compounds are in late stage development with the limited examples including Lyrica (a calcium channel modulator, targets neuropathic pain), umbilical cord blood mononuclear cell transplants (aimed at improving functional recovery) and Procord (autologous activated macrophage therapy, aimed at facilitating neuroprotection and wound healing). However, none of these molecules are expected to reach the market before 2017.
Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS), also referred to as motor neuron disease and Lou Gehrig's disease, is the most common form of the motor neuron diseases. The disorder is characterised by rapidly progressive weakness, muscle atrophy, twitching and spasticity, difficulty with speaking and swallowing and a decline in breathing ability. The defining feature of ALS is the death of both upper and lower motor neurons in the motor cortex of the brain, the brain stem, and the spinal cord. The disease has its onset usually in midlife and leads to death within 3-5 years from diagnosis, usually due to respiratory failure. Once diagnosed, only 10% of patients survive for longer than 10 years. In the US, there are approximately 30,000 ALS sufferers, with 5,000 new cases each year.
There is no curative therapy for ALS and palliative care remains the most important means of treatment. Riluzole is currently the only treatment found to improve survival, by 3-5 months, but patients do not report any subjective improvement. The mechanism of riluzole action is a matter of debate and was originally proposed to act as a sodium channel blocker, associated with damaged neurons, so reducing the influx of calcium ions and indirectly preventing the stimulation of glutamate receptors. However, no binding of riluzole to any receptor has been shown and its anti-glutamate action is still detectable in the presence of sodium channel blockers.
There are currently several ongoing clinical trials for novel ALS treatments. Dexpramipexole has been shown to improve mitochondrial function and to confer significant cellular protection in neurons under stress. A Phase II clinical trial, of dexpramipexole, showed a slowing of ALS disease progression, with a Phase III trial now initiated. Edaravone, a free radical scavenger, is currently in Phase III trial for ALS, with initial results suggesting a slowing in disease progression.
Stroke
Stroke is the rapid loss of brain function due to a disturbance in the blood supply to the brain. This may be caused by a blockage (ischemic stroke) or by a rupture to a blood vessel or an abnormal vasculature (hemorrhagic). Approximately 87% of strokes are caused by ischemia and the remainder by hemorrhage. Stroke is currently the second leading cause of death in the Western world, after heart disease and before cancer, causing ˜10% of deaths worldwide. Stroke can affect patients physically, mentally and emotionally, the extent of which is dependent upon the size and location of the lesion. Disability affects 75% of stroke patients enough to decrease their employability. Physical disabilities can include muscle weakness, numbness, speech and vision loss. Post-stroke emotional disabilities include anxiety, panic attacks, apathy and psychosis. Depression is also commonly reported, affecting 30-50% of stroke survivors.
Immediate treatment for stroke is dependent upon the cause (ischemic or hemorrhagic) and may require surgery, for example, to remove a blood clot or to repair a bleed. To date, the only clinically approved therapy for stroke is treatment with recombinant tissue plasminogen activator (tPA) and other drugs, such as dipyridamole and clopidogrel may be used only in the secondary prevention of stroke in patients with previous history of ischemic events. However tPA treatment must be provided within a limited timeframe after stroke onset and novel strategies are required for neuroprotection rather than clot dissolution. The major disadvantage of tPA therapy is the increased incidence of hemorrhagic transformation and thus only a fraction of patients, approximately 5% are suitable for receiving tPA therapy. Rehabilitation, to regain and relearn skills, is typically required by most stroke patients and usually involves a multidisciplinary team with activities such as physical, occupational and speech therapy. For those stroke sufferers who have been severely affected, nursing care may also be required to provide, for example, feeding, hydration and body positioning.
There remains a significant unmet need for effective and specific therapies delaying and alleviating the symptoms of neurodegenerative diseases.
Neuronal Ceroid Lipofuscinoses
Neuronal ceroid lipofuscinoses (NGLs) are the most common group of neurodegenerative diseases affecting children, with an incidence of up to 1:12500. There are at least eight different childhood forms of NCL, distinguished by the age of onset and the genetic defect, and three adult disease forms. The exact physiological functions of the NCL proteins remain unclear.
Neuroinflammation is an early change in NCL affected animals and humans and it is believed that this is likely to have a substantial role in subsequent neuronal cell loss. Aggregates form in the lysosomes in all NCL forms. Neuronal degeneration and glial activation lead to motor dysfunction, cognitive dysfunction and seizures. There is no effective treatment or cure for the NCLs.
The function of the protein encoding the Cln5 gene, causative of the CLN5 disease form of NCL, remains unknown. Cln5 mutations cause a variant late-infantile human disease and some cases of juvenile and adult clinical disease. Cln5 is a soluble protein located in the lysosomes.